WO 2005/037843 describes partially saturated quinazolines anellated with heteroaryls as kinase inhibitors.
WO 2012/010704 and WO 2013/110585 describe 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors.
The aim of the present invention is to provide new compounds which can be used for the prevention and/or treatment of diseases characterised by excessive or abnormal cell proliferation. The compounds (I) according to the invention are characterised by a powerful inhibitory effect on the kinase activity of the IGF-1 receptor (IGF-1R) and insulin receptor (IR) and a high efficacy against tumour cells, e.g. EWING'S sarcoma, glioblastoma, colorectal cancer etc., which is mediated through the inhibition of phosphorylation of the receptor. In addition to the inhibitory effect and cell activity, compounds (I) show good solubility. In summary, the profile of compounds (I) according to the invention for the first time combines high inhibitory effect on the target IGF-1R, high cellular potency on cancer cells, fine-tuned DMPK properties optimized to prevent or minimize adverse effects immanent to the treatment with IGF1-R/IR inhibitors, e.g. hyperglycemia, and good selectivity over other kinases of the human kinome. Compounds (I) according to the invention are neither anticipated by structurally-related prior art compounds disclosed in patent applications cited hereinbefore or elsewhere nor is there teaching or suggestion which would have guided the skilled person. The inventors had to take every endeavor to provide compounds (I) with these balanced properties.
The insulin-like growth factor (IGF) and insulin signalling network is a highly conserved and essential pathway involved in biological processes including growth, metabolism and homeostasis. In addition, deregulated signalling via this network can enhance tumorigenesis and metastasis of certain cancers.
The ligands IGF-1, IGF-2 and insulin are highly homologous and activate specific hetero or homodimers of the IGF-1R and IR. Following ligand binding, the IGF-1R and IR undergo autophosphorylation mediated via the receptor tyrosine kinase domains. The phosphorylated receptors activate the canonical Ras-Raf-MEK-ERK1/2 and PI3K-PDK1-Akt intracellular signalling cascades, which leads to oncogenic cell proliferation, growth and survival. In addition, activation of the IR by insulin stimulates the uptake of glucose and storage of glycogen in metabolic tissues such as the liver, adipose and muscle.
Published research articles as well as medical and epidemiological investigations have identified a strong correlation between expression of the IGF-1R and IR and ligands for these receptors in tumor development and progression. Intrinsic dependence can be mediated via dysregulated gene or protein expression, function or genetic alteration of the IGF-1R, IR, IGF ligands (IGF1 and IGF2), insulin or other key pathway components including IGF-binding proteins (IGFBPs), IGF2R, IGFBP proteases and/or micro RNAs and RNA binding proteins.
Developing a small molecule competitive inhibitor of the ATP-binding pocket of the IGF-1R and IR as a means of blocking growth and survival signalling cascades in cancer is therefore desirable. The anticipated clinical benefit of blocking such an interaction would be to reduce tumor proliferation, growth and survival and potentially sensitize tumors to cytotoxic agents or targeted therapies.